1-alkyl-4-(beta-hydroxyethyl-amino)-piperidine benzoates



Patented July 19, 1949 Egbert 13d Th fcoriiiifatlori of Miliigan Claims.(Chi-260 2 94) This invention relates to benzoates of l-alkyl-4-(B-hydroxyethylamino)-piperidines and salts thereof with acids.

It is an object of this invention to provide new derivatives of1-a1ky1-4- (p-hydroxyethylamino) piperidines having a variety of uses inthe industrial arts and in particular in the pharmaceutical field.Additional objects will become apparent hereinafter.

The compounds are obtained by heating together al-alkyl--(e-hydroxyethylamino)-piperidine with benzoic acid or benzoicacid derivatives to prepare the esters of the present invention. Thebenzoic acid, or acid derivatives such as the acid chloride or acidanhydride, may be substituted in the ring by one or more groups such ashydroxyl, alkoxyl, alkyl, amino or nitro groups. Reflux temperature ispreferred for rapid completion of the reaction, but other temperaturesmay be used.

The invention may be more readily understood by a consideration of thefollowing illustrative examples.

Example 1.--1 -ethyZ-4- (p-hydroscyethylamino) piperidine Eleven andthree-tenths grams of p-aminoethanol and 23.5 grams of1-ethy1-4-piperidone [J. Am. Chem. Soc. 68, 1239 (1946)] were mixed atroom temperature. One hundred milliliters of absolute alcohol was thenadded and the solution hydrogenated in a suitable apparatus at roomtemperature and an initial hydrogen pressure of 50 pounds per squareinch using platinum oxide as catalyst. After absorption of hydrogen hadceased, the catalyst was removed by filtration and the filtratefractionally distilled. There was thus obtained 15.8 grams ofl-ethyl-4-(fi-hydroxyethylamino) -piperidine, boiling at 117-119 degreescentigrade at a pressure of 17 milimeters of mercury. The dipicratemelted with decomposition at 217-219 degrees centigrade.

Example 2.-1-ethyl-4- (,B-hydroxyethylamino) piperidine benzoate andsalts thereof One and seventy-two one-hundredths grams of 1-ethyl-4-(ii-hydroxyethylamino) -piperidine dissolved in 25 milliliters ofmethylene chloride was mixed with 1.4 milliliters of benzoyl chloride. A

white solid appeared in a short time. After boilg 2.13 ing under-refluxfor about ten mmatesr the mik ture was evaporated to dryness. Theresidue was crystallized from methanol to give needles of1-ethyl-4-(fi-hydroxyethylamino) piperidine benzoate dihydrochloride,melting at 235 degrees centigrade with decomposition.

Alternatively, the dihydrochloride may be transformed into the free baseby mild treatment with alkali, the free base thereafter being extractedfrom solution and distilled at reduced pressure. Other salts may beprepared from the free bases of the present invention by neutralizationwith acids such as picric, hydrobromic, sulfuric, acetic, propionic,citric, and tartaric and crystallization from methanol or evaporation ofthe solution to dryness.

Example 3. 1-ethyl-4- (B-hydroazyethylamino) piperidine p-ethomybenzoateand salts thereof The above procedure is repeated but instead of benzoylchloride an equivalent of p-ethoxybenzoyl chloride is used. The productobtained is 1-ethyl-4- (/3-hydroxyethylamino) -piperidinep-ethoxybenzoate dihydrochloride. Similiarly, p-methoxybenzoyl chlorideand p-propoxybenzoyl chloride give the corresponding l-ethyl-4-(l3-hydroxyethylamino) piperidine p alkoxybenzoate dihydrochlorides.

Example 4.-1 -ethyl-4- e-hydromyethylamino) piperidine P-nitrobenzoateand p-aminobenzoate and salts thereof In the same manner as in Example2, an equivalent amount of p-nitrobenzoyl chloride is used. Theresulting p-nitrobenzoate of 1-ethyl-4-(phydroxyethylamino) -piperidine,when reduced with hydrogen under pressure and platinum oxide as acatalyst, gives the p-aminobenzoate of 1-ethyl-4- (p-hydroxyethylamino)-piperidine.

Example 5. 1 methyl 4 (B hydroxyethylamino) -piperidine benzoate andsalts thereof In the manner of Example 2, equimolar portions of benzoylchloride and 1-methyl-4-(phydroxyethylamino)-piperidine are refluxedtogether for about fifteen minutes. The white solid 1 methyl 1(e-hydroxyethylamino) -piperidine benzoate dihydrochloride precipitates'and may be crystallized from methanol to give an analytical sample. Thefree base may be recovered by treat benzoic acid derivative, e. g., theacid, the anhydride or acid halide, and the selected l-alky'l-4-(p-hydroxyethylamino)-piperidine as react-. H

ants in the process.

The compounds of this invention are useful for a variety of purposes.They may be employed 7 4 that i limit myself only as defined in theappended claims.

'I claim: 1

1. A compound selected from the group consisting of1-lower-alkyl-4-(p-hydroxyethylamino)- piperidine benzoate and acidsalts thereof.

2. An acid salt of 1-alkyl-4-(fl-hydroxyethy1- amino) -piperidinebenzoate.

3. An acid salt of 1-ethyl-4-(p-hydroxyethylamino) epiperidine benzoate.f 4; f 1 f ethyl 7 4 (fl hydroxyethylamino) piperidine benzoatedihydrochloride.

5. The process for the production of l-alkyl- 4-(,8-hydroxyethylamino)piperidine benzoates as chemical intermediates, as surface agents, or

in pharmaceutical preparations. They are of particular value as localanestheticsyandwhen used for this purpose their solutions may he"administered by injection in the customary manments, tablets, or thelike.

Various modifications may be made in the present invention withoutdeparting from the and salts thereof which includes the step of heatingtogether al-alky1-4-(fi-hydroxyethylamino) piperidine and a compoundselected from the group consisting 'of benzoic acids, benzoic acidhalides, and benzoic acid anhydrides to prepare 20 ner, topicalapplication, or incorporated in ointthe desired 1-alkyl-4-(p-hydroxyethylamino) piperidine benzoate compound.

ROBERT H. REITSEMA.

No references cited.

